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Attention deficit hyperactivity disorder (ADHD) is a prevalent and disabling disorder, mainly characterized by hyperactivity, inattention, and impulsivity, but also by olfactory and memory impairments that frequently persist throughout lifetime. The pathophysiology of ADHD is complex, involving several brain regions and neural pathways including alterations in adenosine neuromodulation. The administration of caffeine (a non-selective adenosine receptor antagonist) and physical exercise have been independently pointed as effective approaches for the management of ADHD symptoms. Here, we evaluated the effects of caffeine consumption (0.3 mg/mL in drinking water) plus physical exercise in running wheels during 6 weeks-starting during either adolescence (30 days old) or adulthood (4-5 months old)-on behavioral performance (including olfactory discrimination, open field, object recognition, and water maze tests) on the brain levels of monoamines (by high-performance liquid chromatography), on proteins related to synaptic plasticity and on brain-derived neurotrophic factor signaling (by Western blot analysis) in spontaneously hypertensive rats (SHRs), a validated animal model of ADHD. SHRs displayed persistent impairments of olfactory and short-term recognition memory from adolescence to adulthood, which were accompanied by lower levels of synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex and hippocampus. The association of caffeine plus physical exercise during adolescence or adulthood restored the olfactory discrimination ability and, in an independent manner, improved short-term recognition memory of SHRs. These benefits were not associated to alterations in locomotor activity or in the hypertensive phenotype. The association of caffeine consumption plus physical exercise during adolescence increased the levels of SNAP-25, syntaxin, and serotonin in the hippocampus and prefrontal cortex, and striatal dopamine levels in SHRs. These results provide new evidence of the potential of caffeine and physical exercise, starting at adolescence or adult life, to improve behavioral impairments and stimulate neuroplasticity in ADHD.

We evaluated the effects of phenylephrine, norepinephrine, angiotensin II, and vasopressin in mesenteric, renal, carotid, and tail arteries, and in perfused mesenteric vascular bed from rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Phenylephrine and angiotensin II were less efficacious in mesenteric arteries from the CLP 6 h and CLP 18 h groups than in preparations from non-septic animals, but no differences were found for norepinephrine and vasopressin between the preparations. In renal arteries, none of the vasoconstrictors had impaired activity in the CLP groups. Nonetheless, carotid arteries from the CLP 18 h group presented reduced reactivity to all vasoconstrictors tested, but only phenylephrine and norepinephrine had their effects reduced in carotid arteries from the CLP 6 h group. Despite the reduced responsiveness to phenylephrine, tail arteries from septic rats were hyperreactive to vasopressin and norepinephrine at 6 h and 18 h after the CLP surgery, respectively. The mesenteric vascular bed from CLP groups was hyporeactive to phenylephrine, norepinephrine, and angiotensin II, but not to vasopressin. The vascular contractility in sepsis varies from the well-described refractoriness, to unaltered or even hyperresponsiveness to vasoconstrictors, depending on the vessel, the vasoactive agent, and the time period evaluated.